Much of our understanding of the cellular regulation of immune mechanisms has come from studies of those "experiments of nature" the immunodeficiency diseases. For many years the biochemical basis of most of these defects was unknown. Recently, however, an association has been made between inherited deficiencies of the enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) and immunodeficiency disease. Until this time no specific role for these enzymes in lymphocyte growth and differentiation had been suspected. Experiments from our laboratory have suggested that the immunodeficient state associated with ADA and PNP deficiency results from the selective phosphorylation by T lymphocytes of the ADA substrate deoxyadenosine and the PNP substrate deoxyguanosine leading to the intracellular accumulation of toxic deoxyribonucleotide triphosphates. On the basis of these results, the present investigations propose 1) to delineate further the biochemical mechanisms by which deoxyadenosine and deoxyguanosine produce lymphospecific toxicity in man, 2) to develop new treatments which may be able to reverse the immunodeficient state at the biochemical level, 3) to determine if deficiencies of other deoxyribonucleoside catabolic enzymes can also produce immunodeficiency, e.g., thymidine phosphorylase, 4) to use our newfound knowledge of the biochemistry of immunodeficiency disease for the development of new chemotherapeutic agents capable of modifying the immune response in man without being generally cytotoxic.